Current hypotheses on the pathophysiology of schizophrenia point to the involvement of monoamines like DA, NA and 5-HT. Mass spectrometric methods for the determination of monoamine metabolites such as, HVA, HMPG and 5-HIAA as well as CPZ in CSF and brain have been developed in our laboratory. In psychotic patients treatment with antipsychotic drugs induced a selective and marked elevation of the HVA level in CSF which, in acute psychotic patients, appeared to be related to a positive therapeutic outcome. The first part. Part of the present project concerns a detailed analysis of the relations between antipsychotic and extrapyramidal effects, acceleration of brain DA synthesis and pharmacokinetics in drug treated psychotic patients. Currently available methods for determination of brain monoamine turnover in man, by measuring resting levels or probenecid induced elevations of metabolite levels in CSF, give only a rough index of turnover. Therefore the development of quantitative non-toxic methods for turnover determination is required. The availability of mass spectrometric methods for the determination of monoamine metabolites presents the possibility of using stable isotopes for the in vivo labelling of brain monoamines in man. The monoamines are formed from dietary amino acids by specific hydroxylases using molecular oxygen. At the Weizmann Institute of Science, Israel, the oxygen isotope 018 is available in amounts permitting in vivo exposure of man to atmospheres enriched with 018. In a series of collaborative studies we have demonstrated that following exposure of rats and baboons to an 018 sub 2 atmosphere the DA metabolite, HVA, in brain, CSF and urine is labelled to a large extent with 018. The rate of labelling reflects dynamic changes of brain dopamine metabolism. The second part. Part of the present project concerns an extended collaborative study of in vivo 018 incorporation and turnover of dopamine, noradrenaline and 5-hydroxytryptamine and their major metabolites in animals. The work aims at studying the prerequisites for using 018 for determination of brain monoamine turnover in man.